This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
Compounds that bind to such receptors are likely to be useful in the treatment of diseases mediated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatment of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus.
Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468, EP 506478 and J. Med. Chem. 1993, 36, 2833-2850 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
According to the invention there is provided compounds of formula I: 
wherein A represents a single bond, C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, which alkylene, alkenylene or alkynylene groups are optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, halo or OH;
D represents H, OH, CN, N(R4)(R5), N(H)R6, C(O)N(R4)(R5), C(O)OR7, C(O)R8, C(xe2x95x90NR9a)R8, or C(xe2x95x90NOR9b)R8; provided that when A represents C2-4 alkenylene or C2-4 alkynylene, and D represents OH, N(R4)(R5) or N(H)R6, then D is not directly attached to an unsaturated carbon atom;
and provided that when A represents a single bond, then D does not represent H, OH, N(R4)(R5) or N(H)R6;
R4 and R5 independently represent H, C1-6 alkyl, C3-8 cycloalkyl, aryl,
C1-4 alkylphenyl, which latter four groups are optionally substituted by one or more substituents selected from nitro, halo, C1-4 alkyl or C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms), or R4 and R5, together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic ring, which ring optionally contains one or more additional heteroatoms selected from oxygen, nitrogen and sulfur and which ring is optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, OH, xe2x95x90O, nitro, amino or halo;
R6 represents C(O)R10a, C(O)OR10b or S(O)2R10c;
R10a to R10c independently represent C1-4 alkyl, C3-8 cycloalkyl, aryl, C1-4 alkylphenyl (which four groups are all optionally substituted by or one or more substituents selected from nitro, halo, C1-4 alkyl or C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms)), or R10a represents H;
R7 and R8 independently represent H, C1-6 alkyl, C3-8 cycloalkyl, aryl or C1-4 alkylphenyl, which latter four groups are optionally substituted by one or more substituents selected from nitro, halo, C1-4 alkyl or C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
R9a and R9b independently represent C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-4 alkylphenyl, which latter four groups are optionally substituted by one or more substituents selected from nitro, halo, C1-4 alkyl or C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms), or R9b represents H;
R1 and R2 are each independently H or C1-4 alkyl;
R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy, C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and xe2x80x94N(R11a)(R11b)), C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR11c, S(O)pR11d, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R12a)S(O)2R13, Het1, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R12b)(R12c);
p is 0, 1 or 2;
W represents a single bond, C(O) or S(O)q;
A1 represents a single bond or C1-10 alkylene;
provided that when both W and A1 represent single bonds, then the group xe2x80x94N(R12b)(R12c) is not directly attached to an unsaturated carbon atom;
q is 0, 1 or 2;
R11a to R11d each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het2;
provided that R11d does not represent H when p represents 1 or 2;
R12a to R12c each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het3, or R12b and R12c together represent unbranched C2-6 alkylene which alkylene group is optionally interrupted by O, S and/or an N(R14) group and is optionally substituted by one or more C1-4 alkyl groups;
R13 represents C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, OH, nitro, amino or halo;
R14 represents H, C1-6 alkyl, C3-8 cycloalkyl, A2-(C3-8 cycloalkyl) or A2-aryl;
A2 represents C1-6 alkylene;
Het1, Het2 and Het3 independently represent 3- to 8-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, xe2x95x90O, nitro, amino, halo, CN, aryl, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms);
X is H, halo, C1-4 alkyl or C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
n is 0, 1 or 2;
or pharmaceutically, or veterinarily, acceptable derivatives thereof; which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the invention.xe2x80x9d